Summary The morbidity and mortality caused by antibiotic-resistant bacteria in the United States is staggering, and we are losing our ability to effectively treat these bacterial infections. Initiatives such as antibiotic stewardship programs (ASPs), which consist of coordinated interventions to reduce unnecessary use of antimicrobials, are underway to preserve the effectiveness of the antibiotics that we do have. However, comprehensive studies to assess whether ASPs are effective at achieving their intended goals to reduce resistance in real-world settings are extremely limited. Equally important, we do not know the indirect effects of ASPs on resistance and whether ASPs contribute to unintended negative consequences. Therefore, we will evaluate the changes in consumption of targeted ASP drugs pre- and post-ASP and the changes in inpatient infection rates with clinically important drug-resistant organisms (DROs) pre- and post-ASP. Kaiser Permanente Southern California was one of the first organizations to implement a standardized, regional ASP across many hospitals. Additionally, ASP was introduced at different times during the study period across our 10 hospitals, which offers us unique opportunities for analyses and validation. Methods: We will conduct a retrospective cohort study including all KPSC members seen in any of 10 KPSC hospitals aged ? 18 years who were inpatients from January 1, 2008 through December 31, 2016. We will use multilevel staggered implementation models to evaluate changes in antibiotic consumption and rates of infection with DROs pre- and post-ASP, adjusting for patient-, ASP program-, and hospital-level covariates, as well as time and cluster effects. Impact: The federal recommendations for ASPs, issued only a year ago, herald what will be a large expansion of ASPs worldwide. This timely study will provide an evidence base to support or refute these recommendations. Our results may reveal decreases, increases, or no effect of ASPs on DRO rates. We will also explore how and why changes may occur by estimating indirect effects of volume changes of individual drugs, the rate of change of infection rates, and the role of important covariates such as ASP staffing and other individual and hospital-level characteristics including age, sex, and race/ethnicity.